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Mar. Drugs 2015, 13(2), 824-837; doi:10.3390/md13020824

Synthesis and Biological Evaluation of Carbocyclic Analogues of Pachastrissamine

College of Pharmacy, Seoul National University, Seoul 151-742, Korea
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Author to whom correspondence should be addressed.
Academic Editors: Friedemann Honecker and Sergey A. Dyshlovoy
Received: 8 January 2015 / Revised: 20 January 2015 / Accepted: 26 January 2015 / Published: 3 February 2015
(This article belongs to the Collection Marine Compounds and Cancer)
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Abstract

A series of carbocyclic analogues of naturally-occurring marine sphingolipid pachastrissamine were prepared and biologically evaluated. The analogues were efficiently synthesized via a tandem enyne/diene-ene metathesis reaction as a key step. We found that the analogue 4b exhibited comparable cytotoxicity and more potent inhibitory activity against sphingosine kinases, compared to pachastrissamine. Molecular modeling studies were conducted to provide more detailed insight into the binding mode of 4b in sphingosine kinase. In our docking model, pachastrissamine and 4b were able to effectively bind to the binding pocket of sphingosine kinase 1 as co-crystalized sphingosine. However, 4b showed a hydrophobic interaction with Phe192, which suggests that it contributes to its increased inhibitory activity against sphingosine kinase 1. View Full-Text
Keywords: pachastrissamine; jaspine B; carbocyclic analogue; cytotoxicity; sphingosine kinase inhibitor; molecular modeling pachastrissamine; jaspine B; carbocyclic analogue; cytotoxicity; sphingosine kinase inhibitor; molecular modeling
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Kwon, Y.; Song, J.; Bae, H.; Kim, W.-J.; Lee, J.-Y.; Han, G.-H.; Lee, S.K.; Kim, S. Synthesis and Biological Evaluation of Carbocyclic Analogues of Pachastrissamine. Mar. Drugs 2015, 13, 824-837.

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